Ambulatory function and fatigue in nusinersen-treated children with spinal muscular atrophy. (P2.322)

Objective: To examine distance walked and fatigue during the six minute walk test (6MWT) in nusinersen-treated children with spinal muscular atrophy (SMA). Background: Individuals with milder SMA phenotypes are able to walk but weakness causes gait impairments and reduced endurance. Assessments of walking ability are clinically relevant in this population. The 6MWT is a valid and reliable functional outcome measure that captures weakness and fatigue in SMA patients. Design/Methods: Two multicenter, open-label clinical trials with nusinersen enrolled patients with SMA types 2 and 3, ages 2–15 years. CS2 (NCT01703988) was an 85-day (+168-day follow up [FU]) phase 1b/2a, multiple ascending dose (3, 6, 9 or 12 mg) study, where participants had an option to continue. After a varying treatment break, CS2 patients were enrolled later in the ongoing 533-day (+182-day FU) CS12 (NCT02052791, 12 mg dose) extension study. We evaluated change in 6MWT distance and fatigue over 253 and 1050 days. Fatigue was defined as the change in the 6MWT distance in the sixth minute as compared to the first minute, expressed as a percent. Results: Fourteen subjects were ambulatory during CS2 or CS12 and performed the 6MWT. Baseline characteristics were mean age of symptom onset 23.9 months; mean age at screening 8.6 years; 3 SMN2 copies, n=9; 4 SMN2 copies, n=5. Median (min, max) distance measured (meters) at baseline was 250.5 (0, 563). Median (min, max) distance walked (meters) increased over time by 17 (−47, 99) at Day 253 and 99.0 (31, 150) at Day 1050. Median (min, max) fatigue at baseline was 14.8 (−16, 100) %. Median (min, max) fatigue (%) decreased by 0.1 (−63, 33) at Day 253, and by 3.8 (−86, 20) at Day 1050. Conclusions: Nusinersen-treated ambulatory children demonstrated improvements in ambulatory function, as determined by 6MWT, with increases in walking distance and decreases in fatigue. Study Supported by: Biogen MA, Inc Disclosure: Dr. Montes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Biogen MA, inc, F. Hoffmann-La Roche. Dr. Dunaway has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Mazzone has nothing to disclose. Dr. Pasternak has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Scientific advisory board for Avexis Pharmaceuticals. Dr. Glanzman has nothing to disclose. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting fees and travel costs from AveXis, Biogen, Catabasis, Ionis, Mitobridge, and Summit. Dr. Finkel has received research support from My institution received research support to perform clinical trials from Biogen, BMS, Catabasis, Cytokinetics, Ionis, Lilly, ReveraGen, Sarepta, and Summit. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Darras has served as an ad hoc scientific advisory board member for AveXis, Biogen, Cytokinetics, Marathon Pharmaceuticals, PTC Therapeutics, Roche, and Sarepta; and has been an advisor for Bristol-Myers Squibb and Ionis Pharmaceuticals, Inc.; he has. Dr. Darras has received research support from Dr. Darras has received research support from from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, CS2/CS12 studies, from Biogen for CS11 , as well as from Cytokinetics, PTC Therapeutics, Fibrogen and Summit. Dr. Muntoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Participation to SAB meetings (Roche; Avexis and Biogen) and educational activities (Biogen). Dr. Muntoni has received research support from My institute receives support for Biogen and Roche sponsored clinical trials. Dr. Mercuri has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen MA, Inc, Ionis Pharmaceuticals, Inc. & F. Hoffman La-Roche Ltd. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting/Advisory Board membership with AveXis, Biogen, Sarepta, PTC, Cytokinetics, Ultragenyx, and Sanofi. Dr. De Vivo has received research support from Clinical trials support from Sarepta, PTC, Ultragenyx, and Biogen, animal model licensing to Sanofi. Dr. Bishop has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Full-time employee of Otonomy Inc. Dr. Schneider has nothing to disclose. Dr. Bennett has nothing to disclose. Dr. Foster has nothing to disclose. Dr. Farwell has nothing to disclose.